Hayee, B.; (2010) Neutrophil function and bacterial clearance in Crohn’s disease. Doctoral thesis , UCL (University College London).

Abstract

The aetiology of Crohn’s disease (CD), a chronic inflammatory disorder primarily affecting the gastro-intestinal tract, remains obscure. The prevailing hypothesis centres on an aberrant adaptive immune response to intestinal bacteria. Intestinal lesions in CD are associated with granuloma formation, suggesting the persistence of antigenic (infectious) material. Perianal involvement (PI) in CD, in particular, is characterised by overt infection and abscess formation. However, to date no single infectious aetiology has been demonstrated. Inherited disorders of neutrophil function are associated with non-infectious, granulomatous, intestinal inflammation that is indistinguishable from CD in up to 50% of cases. Of these, 75-100% have PI. In these conditions, impaired clearance of bacteria occurs as a consequence, and intestinal inflammation arises without aberrant adaptive immune responses. Neutrophil dysfunction (inherited or otherwise) may contribute to the pathogenesis of both intestinal and perianal involvement in CD. Impaired neutrophil influx to sites of acute inflammation (induced by traumatic stimuli) has been demonstrated in CD. An inferred defect in bacterial clearance would provide a trigger for the induction of a granulomatous chronic inflammatory response, as it does in the inherited disorders of neutrophil function. Although other aspects of neutrophil function have been studied with respect to the pathogenesis of CD, the literature provides conflicting conclusions and it is unclear whether a primary neutrophil dysfunction could contribute. The work in this thesis tests the hypothesis that bacterial clearance is abnormal in CD, as well as investigating key aspects of neutrophil function in large cohorts of patients with intestinal and perianal involvement. For the first time, neutrophil influx to – and subsequent clearance of – E. coli in CD is shown to be attenuated in vivo, while – very significantly – the clearance of S. aureus is normal. Study of the neutrophil respiratory burst, however, reveals a small number of patients with undiagnosed primary neutrophil disorders (investigated further). In patients with perianal involvement, neutrophil adhesion is found to be defective and may be related to the lipid composition of plasma membranes. This would contribute to impaired neutrophil influx and bacterial persistence – leading to overt infection. In conclusion, although neutrophil function is likely to be normal in the majority of patients with CD, it may explain the development of PI. Furthermore, a small but significant group of patients with presumed ‘idiopathic’ CD may have an underlying inherited neutrophil defect. It is important to identify these patients in order to alter their treatment from the usual anti-inflammatory or immunosuppressive therapies commonly employed for CD. Bacterial persistence is likely to be a primary pathogenic phenomenon in CD and offers targets for therapeutic intervention.

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